Associations between nephron number and podometrics in human kidneys
Authors: Kotaro Haruhara, Go Kanzaki, Takaya Sasaki, Saeko Hatanaka, Yusuke Okabayashi, Victor G. Puelles, Ian S. Harper, Akira Shimizu, Luise A. Cullen-McEwen, Nobuo Tsuboi, Takashi Yokoo, John F. Bertram
Journal: Kidney International (2022)

Podocyte loss and resultant nephron loss are common processes in the development of glomerulosclerosis and chronic kidney disease. While the cortical distribution of glomerulosclerosis is known to be non-uniform, the relationship between the numbers of non-sclerotic glomeruli (NSG), podometrics and zonal differences in podometrics remain incompletely understood. To help define this, we studied autopsy kidneys from 50 adults with median age 68 years and median eGFR 73.5 mL/min/1.73m2 without apparent glomerular disease in a cross-sectional analysis. The number of NSG per kidney was estimated using the physical dissector/fractionator combination, while podometrics were estimated using model-based stereology. The number of NSG per kidney was directly correlated with podocyte number per tuft and podocyte density. Each additional 100,000 NSG per kidney was associated with 26 more podocytes per glomerulus and 16 podocytes per 106 μm3 increase in podocyte density. These associations were independent of clinical factors and cortical zone. While podocyte number per glomerulus was similar in the three zones, superficial glomeruli were the smallest and had the highest podocyte density but smallest podocytes. Increasing age and hypertension were associated with lower podocyte number, with age mostly affecting superficial glomeruli, and hypertension mostly affecting juxtamedullary glomeruli. Thus, in this first study to report a direct correlation between the number of NSG and podometrics, we suggest that podocyte number is decreasing in NSG of individuals losing nephrons. However, another possible interpretation may be that more nephrons might protect against further podocyte loss. Podocyte loss and resultant nephron loss are common processes in the development of glomerulosclerosis and chronic kidney disease. While the cortical distribution of glomerulosclerosis is known to be non-uniform, the relationship between the numbers of non-sclerotic glomeruli (NSG), podometrics and zonal differences in podometrics remain incompletely understood. To help define this, we studied autopsy kidneys from 50 adults with median age 68 years and median eGFR 73.5 mL/min/1.73m2 without apparent glomerular disease in a cross-sectional analysis. The number of NSG per kidney was estimated using the physical dissector/fractionator combination, while podometrics were estimated using model-based stereology. The number of NSG per kidney was directly correlated with podocyte number per tuft and podocyte density. Each additional 100,000 NSG per kidney was associated with 26 more podocytes per glomerulus and 16 podocytes per 106 μm3 increase in podocyte density. These associations were independent of clinical factors and cortical zone. While podocyte number per glomerulus was similar in the three zones, superficial glomeruli were the smallest and had the highest podocyte density but smallest podocytes. Increasing age and hypertension were associated with lower podocyte number, with age mostly affecting superficial glomeruli, and hypertension mostly affecting juxtamedullary glomeruli. Thus, in this first study to report a direct correlation between the number of NSG and podometrics, we suggest that podocyte number is decreasing in NSG of individuals losing nephrons. However, another possible interpretation may be that more nephrons might protect against further podocyte loss. Nephron endowment in humans is established at around 36 weeks of gestation when nephrogenesis ceases.1Hinchliffe S.A. Sargent P.H. Howard C.V. et al.Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle.Lab Invest. 1991; 64: 777-784PubMed Google Scholar,2Ryan D. Sutherland M.R. Flores T.J. et al.Development of the human fetal kidney from mid to late gestation in male and female infants.EBioMedicine. 2018; 27: 275-283Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar In normal adult kidneys, nephron number varies approximately 13-fold.3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar This variation is the product of initial differences in nephron endowment and age-related nephron loss.4Zhang Z. Quinlan J. Hoy W. et al.A common RET variant is associated with reduced newborn kidney size and function.J Am Soc Nephrol. 2008; 19: 2027-2034Crossref PubMed Scopus (106) Google Scholar, 5Hoy W.E. Douglas-Denton R.N. Hughson M.D. et al.A stereological study of glomerular number and volume: preliminary findings in a multiracial study of kidneys at autopsy.Kidney Int Suppl. 2003; : S31-S37Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 6Denic A. Lieske J.C. Chakkera H.A. et al.The substantial loss of nephrons in healthy human kidneys with aging.J Am Soc Nephrol. 2017; 28: 313-320Crossref PubMed Scopus (192) Google Scholar Brenner et al.7Brenner B.M. Garcia D.L. Anderson S. Glomeruli and blood pressure: less of one, more the other?.Am J Hypertens. 1988; 1: 335-347Crossref PubMed Scopus (1080) Google Scholar first proposed that low nephron number, either congenital or acquired, may predispose to subsequent development of hypertension and chronic kidney disease, and findings from human and animal studies generally support this proposal. In addition to nephron loss, podocyte loss as a result of healthy aging and hypertension can also lead to glomerular pathology and loss, typically featuring ischemic-appearing glomeruli and globally sclerotic glomeruli.8Hodgin J.B. Bitzer M. Wickman L. et al.Glomerular aging and focal global glomerulosclerosis: a podometric perspective.J Am Soc Nephrol. 2015; 26: 3162-3178Crossref PubMed Scopus (136) Google Scholar, 9Puelles V.G. Cullen-McEwen L.A. Taylor G.E. et al.Human podocyte depletion in association with older age and hypertension.Am J Physiol Renal Physiol. 2016; 310: F656-F668Crossref PubMed Scopus (44) Google Scholar, 10Haruhara K. Sasaki T. de Zoysa N. et al.Podometrics in Japanese living donor kidneys: associations with nephron number, age, and hypertension.J Am Soc Nephrol. 2021; 32: 1187-1199Crossref PubMed Scopus (5) Google Scholar, 11Naik A.S. Le D. Aqeel J. et al.Podocyte stress and detachment measured in urine are related to mean arterial pressure in healthy humans.Kidney Int. 2020; 98: 699-707Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 12Denic A. Ricaurte L. Lopez C.L. et al.Glomerular volume and glomerulosclerosis at different depths within the human kidney.J Am Soc Nephrol. 2019; 30: 1471-1480Crossref PubMed Scopus (19) Google Scholar However, unlike nephron endowment, the concept of podocyte endowment, a term first coined by Puelles et al.13Puelles V.G. Douglas-Denton R.N. Cullen-McEwen L.A. et al.Podocyte number in children and adults: associations with glomerular size and numbers of other glomerular resident cells.J Am Soc Nephrol. 2015; 26: 2277-2288Crossref PubMed Scopus (48) Google Scholar has been little studied. Puelles et al.13Puelles V.G. Douglas-Denton R.N. Cullen-McEwen L.A. et al.Podocyte number in children and adults: associations with glomerular size and numbers of other glomerular resident cells.J Am Soc Nephrol. 2015; 26: 2277-2288Crossref PubMed Scopus (48) Google Scholar found that glomeruli of children contained approximately 100 fewer podocytes per glomerulus than adults. We have recently shown in animal studies that maternal hypoxia and maternal low protein diet both give rise to offspring with low nephron endowment as well as low podocyte endowment.14Gonçalves G.D. Walton S.L. Gazzard S.E. et al.Maternal hypoxia developmentally programs low podocyte endowment in male, but not female offspring.Anat Rec (Hoboken). 2020; 303: 2668-2678Crossref PubMed Scopus (8) Google Scholar,15Cullen-McEwen L.A. van der Wolde J. Haruhara K. et al.Podocyte endowment and the impact of adult body size on kidney health.Am J Physiol Renal Physiol. 2021; 321: F322-F334Crossref PubMed Scopus (5) Google Scholar These findings raise the questions of whether kidneys with higher nephron number also have glomeruli with higher podocyte number, thereby providing 2 forms of protection against nephron loss, and whether kidneys with lower nephron number have fewer podocytes per glomerulus thus increasing the risk of further nephron loss. In the present study, we estimated the total number of nonsclerotic glomeruli (NSG) as well as podocyte number per glomerulus in Japanese adult kidneys obtained at autopsy. Given that the distribution of glomerulosclerosis is not uniform through the cortex,12Denic A. Ricaurte L. Lopez C.L. et al.Glomerular volume and glomerulosclerosis at different depths within the human kidney.J Am Soc Nephrol. 2019; 30: 1471-1480Crossref PubMed Scopus (19) Google Scholar,16Sasaki T. Tsuboi N. Okabayashi Y. et al.Synergistic impact of diabetes and hypertension on the progression and distribution of glomerular histopathological lesions.Am J Hypertens. 2019; 32: 900-908Crossref PubMed Scopus (7) Google Scholar we also examined podometrics (podocyte number, volume, and density) in 3 cortical zones (juxtamedullary, middle, superficial). Our findings demonstrate a direct correlation between nephron number and podocyte number, which suggests that subjects who lost fewer podocytes per glomerulus in postnatal life also lost fewer nephrons, while those who lost more podocytes per glomerulus lost more nephrons. An alternative explanation for this finding is that subjects born with more nephrons had a higher podocyte count per glomerulus than did those born with fewer nephrons, implying that perinatal health has a direct impact on offspring kidney health in later life. We also report zonal differences in relation to the effect of age and hypertension on podocyte number. This study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Monash University Human Research Ethics Committee (19070) and the Ethics Review Board of the Jikei University School of Medicine (30-268 [9289]). Kidneys were collected at autopsies conducted at the Nippon Medical School, Tokyo, Japan, between January 1, 2010, and December 31, 2014, as previously described.17Kanzaki G. Puelles V.G. Cullen-McEwen L.A. et al.New insights on glomerular hyperfiltration: a Japanese autopsy study.JCI Insight. 2017; 2: e94334Crossref PubMed Scopus (42) Google Scholar Autopsy kidneys from subjects aged 18 years or more without apparent primary or secondary glomerular diseases were analyzed in the present study. Clinical data were obtained from autopsy records. Body surface area (BSA) for Japanese population was determined using the equation18Fujimoto S. Watanabe T. Studies on the body surface area of Japanese.Acta Med Nagasaki. 1969; 14: 1-13PubMed Google Scholar:BSA (m2) = Weight0.444 (kg) × Height0.663 (cm) × 0.008883 Hypertension was defined as a systolic blood pressure of >140 mm Hg and/or a diastolic blood pressure of >90 mm Hg, or the use of antihypertensive medications. The estimated glomerular filtration rate (eGFR) was calculated using a modified 3-variable equation for estimating the GFR for Japanese population19Matsuo S. Imai E. Horio M. et al.Revised equations for estimated GFR from serum creatinine in Japan.Am J Kidney Dis. 2009; 53: 982-992Abstract Full Text Full Text PDF PubMed Scopus (4442) Google Scholar:eGFR = 194 × Age−0.287 × s-Cre−1.094 (× 0.739, if female)where s-Cre is the serum creatinine level within 1 month before death. Methods used to estimate nephron number per kidney, podocyte density, podocyte number, podocyte volume, and glomerular volume (Figure 1) are described in the Supplementary Methods. Continuous variables are expressed as median (interquartile range [IQR]). Mann-Whitney U tests were used for comparisons between 2 groups, because some clinical variables did not show a Gaussian distribution. For comparisons of data from the 3 cortical zones, the Friedman test with Dunn post hoc analysis was used. For among-group comparisons of 2 × 2 factors, a 2-factorial analysis of variance was used. The Pearson correlation test was used to examine correlations between 2 variables after confirming the variables obeyed the Gaussian distribution by Kolmogorov-Smirnov test. Multiple regression analyses were used to examine relationships between nonsclerotic nephron number and podometrics. In the analysis for the zonal differences in podometrics, sensitivity analyses were performed in younger subjects (median age of 68 years or less), normotensive subjects, subjects with a higher than median number of NSG, and subjects with preserved kidney function (eGFR of 60 ml/min per 1.73 m2 or more). A value of P < 0.05 was considered significant for all statistical tests. Data were analyzed using SPSS software, version 23 (IBM Inc.), and PRISM 9 (GraphPad Software). Initially, kidneys were obtained at autopsy from 63 subjects. However, 13 subjects were excluded, leaving a total of 50 kidneys for the study. The reasons for exclusion were (i) archival paraffin blocks were not available (n = 6), (ii) inadequate immunofluorescence staining for podocyte markers (n = 5), and (iii) missing clinical data (n = 2; Supplementary Figure S1). The clinical characteristics of the included and excluded subjects are shown in Table 1. The clinical characteristics, other than time from death to autopsy, were similar in the 2 groups, as was the number of NSG per kidney (included subjects, 421,547 [IQR: 289,095–548,233] vs. excluded subjects, 345,723 [IQR: 237,783–546,978]; P = 0.2).Table 1Characteristics of the 63 autopsy subjects initially enrolled in the studyVariablesIncluded (n = 50)Excluded (n = 13)P valueAge, yr68.0 (52.5–73.5)70.0 (54.5–72.5)0.9Sex, male30 (60)8 (62)0.9Height, cm163 (156–168)160 (152–168)0.5Body weight, kg56.0 (49.8–66.1)54.0 (46.9–62.1)0.6Body mass index, kg/m221.5 (19.9–24.0)21.1 (17.8–25.9)0.7Body surface area, m21.53 (1.44–1.71)1.54 (1.41–1.60)0.5Hypertension21 (42)4 (33)aData were available for 12 subjects.0.6eGFR, ml/min per 1.73 m273.5 (47.6–88.9)59.4 (47.2–97.2)bData were available for 10 subjects.Values are median (interquartile range) or n (%). Mann-Whitney U tests were used.0.5Time from death to autopsy, h7.4 (3.0–14.0)22.5 (9.0–40.0)0.009eGFR, estimated glomerular filtration rate.a Data were available for 12 subjects.b Data were available for 10 subjects.Values are median (interquartile range) or n (%). Mann-Whitney U tests were used. Open table in a new tab eGFR, estimated glomerular filtration rate. All subjects were Japanese adults. The median age of the 50 included subjects was 68 years with a range from 28 to 85 years. Thirty subjects (60%) were male. A medical history of hypertension and diabetes was identified in 21 subjects (42%) and 5 (10%) respectively. The 5 subjects who were diabetic did not show overt diabetic glomerular changes, such as exudative or nodular lesions. Median eGFR was 73.5 ml/min per 1.73 m2. Reduced renal function (eGFR <60 ml/min per 1.73 m2) was evident in 17 subjects (34%). Male subjects had a larger BSA than female subjects did (male 1.66 m2 vs. female 1.47 m2). There was no significant sex difference in age, prevalence of hypertension, or eGFR. Nephron number, glomerular volume, and podometric data in the 50 autopsy kidneys are shown in Table 2. Median total nephron number was 451,175 (IQR: 318,395–569,008), with values ranging from 78,988 to 987,466. The median number of NSG per subject was 421,547 (IQR: 289,095–548,233), with values ranging from 65,049 to 980,794.Table 2Nephron number, glomerular volume, and podometric data for the 50 included autopsy kidneysVariablesMedian (IQR)Total nephron number, ×103451 (318–569)Nonsclerotic nephron number, ×103421 (289–548)Sclerotic nephron number, ×10324 (15–40)%GGS5.8 (3.4–9.9)Glomerular volume, ×106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar2.37 (1.94–3.31)Podocyte density, per 106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar183 (141–241)Podocyte number per glomerular tuft492 (390–549)Podocyte volume, μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar792 (585–1618)VV(Pod/Glom), %15 (11–19)%GGS, percentage of globally sclerotic glomeruli; IQR, interquartile range; VV(Pod/Glom), proportion of glomerular volume comprised by podocytes. Open table in a new tab %GGS, percentage of globally sclerotic glomeruli; IQR, interquartile range; VV(Pod/Glom), proportion of glomerular volume comprised by podocytes. Median podocyte number per glomerulus was 492, with values ranging from 260 to 694 podocytes per glomerulus. Median podocyte density was 183 per 106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar with values ranging from 78 to 402 per 106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar, and median podocyte volume was 792 μm3 with values ranging from 228 to 1618 μm3. Podocyte number per glomerulus was inversely associated with age (RS = −0.351; P = 0.015), but it was not associated with either BSA or eGFR. There was no significant sex difference in podocyte number per tuft (male 489 [IQR: 389–549] vs. female 502 [IQR: 391–551]; P = 0.9). Hypertensive subjects had significantly fewer podocytes per tuft than normotensive subjects (hypertensive 414 [IQR: 367–517] vs. normotensive 524 [IQR: 438–586]; P = 0.02). In a 2-factorial analysis of variance stratified by age and presence of hypertension, older subjects had significantly fewer podocytes per glomerulus than did younger subjects in the superficial cortex, whereas no differences were found in the other cortical zones. Juxtamedullary glomeruli in hypertensive subjects had fewer podocytes than juxtamedullary glomeruli in normotensive subjects (Figure 2a–d ). Glomerular volume was 36% greater in male subjects than in female subjects (male 2.82 [IQR: 2.05–3.95] × 106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar vs. female 2.08 [IQR: 1.65–2.35] × 106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar; P = 0.001) and was directly correlated with BSA (rp coefficient = 0.307; P = 0.03). On the other hand, podocyte density was 35% lower in male subjects than in female subjects (male 148 [IQR: 136–199] podocytes per 106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar vs. female 229 [IQR: 190–278] podocytes per 106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar; P < 0.001) and was inversely associated with BSA (rp coefficient = −0.323; P = 0.03). Glomerular volume and podocyte density were not significantly associated with age, eGFR, or blood pressure status. Neither podocyte volume nor VV(Pod/Glom) (volume density of podocytes in glomeruli) were associated with age, BSA, or eGFR. However, podocytes in male subjects were 37% larger than in female subjects (male 881 μm3 [IQR: 660–1181] vs. female 645 μm3 [IQR: 495–831]; P = 0.008). VV(Pod/Glom) was similar in both sexes (male 14.7% [IQR: 10.8–17.5] vs. female 14.4% [IQR: 11.4–20.7]; P = 0.6). The clinical characteristics and morphological data of kidneys from subjects who are diabetic and those who are nondiabetic are presented in Supplementary Table S1. The clinical characteristics were similar in the 2 groups. While the total number of glomeruli and the number of nonsclerotic glomeruli were lower in the diabetic group than in the nondiabetic group, these differences were not statistically significant. Glomerular volume was larger in the diabetic group than in the nondiabetic group, while podocyte density was lower and podocyte volume was larger. On the other hand, podocyte number per tuft and VV(Pod/Glom) were similar in the 2 groups. As expected, significant associations between glomerular volume and values for podometric parameters were found (Supplementary Figure S2A–C). Higher glomerular volume was significantly associated with higher podocyte number per tuft, lower podocyte density, and larger podocyte volume. There was no significant relationship between glomerular volume and VV(Pod/Glom) (Supplementary Figure S2D). The number of NSG per kidney was directly correlated with podocyte number per tuft (P < 0.001), podocyte density (P < 0.001) and VV(Pod/Glom) (P = 0.002). Each additional 100,000 NSG per kidney was associated with 26 more podocytes per glomerulus (Figure 3a ), 16 podocytes per 106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar increase in podocyte density (Figure 3b), and a 0.98% increase in the proportion of glomerular volume composed of podocytes (Figure 3d). The number of NSG was not associated with podocyte volume (P = 0.8; Figure 3c). The associations among the number of NSG and podocyte number, podocyte density, and VV(Pod/Glom) remained statistically significant after adjustment for clinical factors including age, sex, BSA, presence of hypertension, and eGFR (Table 3). The number of NSG was significantly associated with these podometric parameters in each cortical zone (Supplementary Figures S3–S5). The number of NSG was not associated with podocyte volume in any cortical zone (data not shown). The relationships between total nephron number and podometrics showed a similar trend to the above-mentioned analyses. In addition, the percentage of globally sclerotic glomeruli was inversely correlated with podocyte number, podocyte density, and VV(Pod/Glom) (Supplementary Figures S6).Table 3Multiple linear regression analyses for podometrics in 50 subjectsUnadjustedModel 1aModel 1 was adjusted for age and sex.Model 2bModel 2 was adjusted for age, sex, body surface area, presence of hypertension, and estimated glomerular filtration rate.PodometricsΒP valueΒP valueβP valuePodocyte number per tuft in whole cortex25.9<0.00127.6<0.00132.50.001Podocyte density in whole cortex16.0<0.00117.7<0.00119.20.002Podocyte volume in whole cortex−12.00.589−14.00.586−6.80.836VV(Pod/Glom) in whole cortex0.980.0021.120.0051.290.008NSG, nonsclerotic glomeruli; VV(Pod/Glom), proportion of glomerular volume comprised by podocytes.Values are the number of NSG (per 105 NSG). The β values were calculated for each 105 of NSG increase.a Model 1 was adjusted for age and sex.b Model 2 was adjusted for age, sex, body surface area, presence of hypertension, and estimated glomerular filtration rate. Open table in a new tab NSG, nonsclerotic glomeruli; VV(Pod/Glom), proportion of glomerular volume comprised by podocytes. Values are the number of NSG (per 105 NSG). The β values were calculated for each 105 of NSG increase. Next, glomerular volume and podometrics in the 3 cortical zones were compared (Table 4). Podocyte number per glomerulus was remarkably similar in the 3 cortical zones, varying by just 8%. Superficial glomeruli were smaller than glomeruli in the other 2 zones and had a higher podocyte density. Median podocyte volume was lower in superficial glomeruli than in the other 2 zones, however VV(Pod/Glom) was similar in the 3 zones. Similar findings were observed in younger subjects (median age of 68 years or less), normotensive subjects, subjects with a higher than median number of NSG, and subjects with preserved kidney function (eGFR of 60 ml/min per 1.73 m2 or more; Supplementary Tables S1 and S2).Table 4Glomerular volume and podometrics in the 3 cortical zones (n = 50)VariablesJuxtamedullaryMiddleSuperficialP valueGlomerular volume, ×106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar2.58 (1.98–3.37)2.49 (1.94–3.79)2.36 (1.46–3.02)aP < 0.01 versus juxtamedullary.,bP < 0.001 versus Middle.<0.001Podocyte number per tuft471 (383–543)505 (395–590)464 (363–548)0.1Podocyte density, n/106 μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar181 (133–220)185 (140–239)209 (143–290)cP < 0.001 versus juxtamedullary.,dP < 0.05 versus middle.<0.001Podocyte volume, μm3Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (321) Google Scholar828 (600–1229)760 (554–1138)672 (486–1016)bP < 0.001 versus Middle.,cP < 0.001 versus juxtamedullary.<0.001VV(Pod/Glom), %15.4 (12.0–18.8)13.9 (11.2–19.0)14.1 (10.4–18.9)0.9VV(Pod/Glom), proportion of glomerular volume comprised by podocytes.Values are median (interquartile range).a P < 0.01 versus juxtamedullary.b P < 0.001 versus Middle.c P < 0.001 versus juxtamedullary.d P < 0.05 versus middle. Open table in a new tab VV(Pod/Glom), proportion of glomerular volume comprised by podocytes. Values are median (interquartile range). Absolute podocyte depletion results from podocyte loss, whereas relative podocyte depletion occurs due to podocyte loss and/or glomerular hypertrophy, the latter occurring due to a range of factors including low nephron endowment at birth,20Wlodek M.E. Mibus A. Tan A. et al.Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat.J Am Soc Nephrol. 2007; 18: 1688-1696Crossref PubMed Scopus (178) Google Scholar,21Hokke S. Arias N. Armitage J.A. et al.Maternal glucose intolerance reduces offspring nephron endowment and increases glomerular volume in adult offspring.Diabetes Metab Res Rev. 2016; 32: 816-826Crossref PubMed Scopus (14) Google Scholar age-related nephron loss,6Denic A. Lieske J.C. Chakkera H.A. et al.The substantial loss of nephrons in healthy human kidneys with aging.J Am Soc Nephrol. 2017; 28: 313-320Crossref PubMed Scopus (192) Google Scholar obesity,12Denic A. Ricaurte L. Lopez C.L. et al.Glomerular volume and glomerulosclerosis at different depths within the human kidney.J Am Soc Nephrol. 2019; 30: 1471-1480Crossref PubMed Scopus (19) Google Scholar,22Denic A. Mathew J. Nagineni V.V. et al.Clinical and pathology findings associate consistently with larger glomerular volume.J Am Soc Nephrol. 2018; 29: 1960-1969Crossref PubMed Scopus (19) Google Scholar hypertension,12Denic A. Ricaurte L. Lopez C.L. et al.Glomerular volume and glomerulosclerosis at different depths within the human kidney.J Am Soc Nephrol. 2019; 30: 1471-1480Crossref PubMed Scopus (19) Google Scholar,16Sasaki T. Tsuboi N. Okabayashi Y. et al.Synergistic impact of diabetes and hypertension on the progression and distribution of glomerular histopathological lesions.Am J Hypertens. 2019; 32: 900-908Crossref PubMed Scopus (7) Google Scholar,22Denic A. Mathew J. Nagineni V.V. et al.Clinical and pathology findings associate consistently with larger glomerular volume.J Am Soc Nephrol. 2018; 29: 1960-1969Crossref PubMed Scopus (19) Google Scholar,23Ellis R.J. Kalma B. Del Vecchio S.J. et al.Chronic kidney cortical damage is associated with baseline kidney function and albuminuria in patients managed with radical nephrectomy for kidney tumours.Pathology. 2019; 51: 32-38Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar and diabetes.12Denic A. Ricaurte L. Lopez C.L. et al.Glomerular volume and glomerulosclerosis at different depths within the human kidney.J Am Soc Nephrol. 2019; 30: 1471-1480Crossref PubMed Scopus (19) Google Scholar,16Sasaki T. Tsuboi N. Okabayashi Y. et al.Synergistic impact of diabetes and hypertension on the progression and distribution of glomerular histopathological lesions.Am J Hypertens. 2019; 32: 900-908Crossref PubMed Scopus (7) Google Scholar,22Denic A. Mathew J. Nagineni V.V. et al.Clinical and pathology findings associate consistently with larger glomerular volume.J Am Soc Nephrol. 2018; 29: 1960-1969Crossref PubMed Scopus (19) Google Scholar,23Ellis R.J. Kalma B. Del Vecchio S.J. et al.Chronic kidney cortical damage is associated with baseline kidney function and albuminuria in patients managed with radical nephrectomy for kidney tumours.Pathology. 2019; 51: 32-38Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Both absolute and relative podocyte depletion are common early events leading to glomerulosclerosis and subsequent reduction in the number of functioning nephrons.24Wharram B.L. Goyal M. Wiggins J.E. et al.Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.J Am Soc Nep